Triethyltin (TET) bromide is a neruotoxic compound that produces CNS edema and muscular dysfunction in man and laboratory animals. Subchronic (2-3 weeks) exposure of rats to TET in drinking water (10-30 mg/L) results in a progressive neuromuscular disorder. Deficiencies are reported in neuromuscular transmission, acetylcholine release, force of contraction, maintenance of resting membrane potential, and energy metabolism. Vacuolar formation in the myelin of the ventral roots and spinal cord accompanies massive intoxication. Axonal degeneration of motoneurons and/or denervation is not extensive although chromatolysis is observed in motoneurons of the lumbar spinal cord. It is postulated that this unusual neuropathy is the result of TET-induced mitochondrial damage. The present proposal will evaluate the validity of this hypothesis in search of the specific mechanism(s) of TET toxicity. Rats will be treated subchronically with TET for up to 28 days. The isolated vascular perfused phrenic nerve-hemidiaphragm (VPRH) and other neuromuscular preparations will be studied at fixed intervals. Metabolism of radiolabelled glucose through glycolysis and the TCA cycle will be analyzed in the contracting VPRH to determine the extent of mitochondrial compromise and compensatory changes in energy metabolism. Data on lactate production, ATP/ADP ratios, and glycogen levels will also provide an assessment of bioenergetic status. Impairment of neuromuscular transmission will be studied by intracellular recording. Electron microscopy will be used to search for ultrastructural correlates to the functional and biochemical alterations observed and to assess mitochondrial integrity. An alternative theory suggest that TET may alter the selective permeability of membranes. Consequently, intracellular [C1-] and [Ca++] and membrane resistances of the myofibers will be measured. Unusual ionic conductances will be identified using patch clamp technology. The activity of membrane Na+,K+-ATPase will be measured; its inhibition could explain the TET-induced non-denervation depolarization observed in vivo in soleus muscle. Lastly, the reversibility of the biochemical, electrophysiological and histological changes will be studied during recovery from TET intoxication. The study of this TET-induced neuromuscular disorder may prove useful in understanding other neurotoxic agents (e.g., arsenic and thallium) and diseases (e.g., myotonia and metabolic myopathies) which may involve abnormalities in energy metabolism and/or membrane transport.